Heart failure remains a leading cause of morbidity and mortality in the United States. Despite advances in medical therapy, a large number of patients with anterior infarcts remodel adversely and develop heart failure. We hypothesize that distinct changes in myofiber architecture play an important role in the pathogenesis of heart failure. We further hypothesize that diffusion tensor MRI (DTI) of the human heart in vivo will allow these changes to be characterized and thereby elucidate the microstructural basis for myocardial remodeling and the development of heart failure. Our group has previously developed a diffusion-encoded stimulated echo pulse sequence to perform DTI of the heart in vivo. Here we will make fundamental enhancements to the sequence to improve its speed, coverage and accuracy. We aim to perform a free-breathing DTI acquisition of the entire heart in vivo in less than 10 minutes. This will involve simultaneous multislice excitation, gradient reordering, and the use of advanced spatiotemporal registration techniques. To characterize changes in myocardial architecture, we will design novel analysis methods tailored to cardiac DTI. This will include the development of metrics for the quantification of myocardial tract and sheet architecture. We hypothesize that these measures, coupled with improvements in image acquisition, will allow subtle changes in myofiber organization to be detected and followed over time, which will help in identifying new targets for therapy. Aim 1 of the proposal will involve pulse sequence refinement to improve image quality and reduce acquisition time. In Aim 2, we will develop new techniques with which to characterize the microstructural changes seen in patients with cardiac remodeling after myocardial infarction (MI). This will include metrics designed to detect the infarct, border, and remote zones, and to characterize the associated microstructural alterations. For each metric, we will determine a set of norms based on the study of healthy volunteers, and also determine the age and load dependence of the developed metric. In Aim 3, patients with recent anterior myocardial infarcts will be studied in a longitudinl fashion. Our preliminary data reveal that significant abnormalities in fiber and sheet architecture are seen in both the border and remote zones in these patients soon after infarction. We will follow these changes over time to better understand their relationship with the development of left ventricular dilation and heart failure. Completion of the study will result in the identificaton of a new panel of phenotypic biomarkers that can characterize myocardial remodeling at the microstructural level and predict the development of heart failure. These biomarkers will play an important role in the development of new therapies designed to prevent and treat heart failure, which will be of major medical and public health significance.